Chronic om licati ns of Diabete With education) patients can prevent or delay some of the more serious complications of diabetes. by Condit F. Steil, PharrnD, CDE
one of the health care changes that have occurred in recent years has been more dramatic than the recognition that chronic disorders have beCOllle a n1ajor concern and that education is the key to dealing with them. The third leading cause of death due to disease in America is the chronic disorder diabetes mellitus and its complications. All of the n1ajor organ systems in the body can be dan1aged by diabetes. Diabetes is the single n10st comn1on cause of renal failure in the United States and is the leading cause of nontraun1atic amputations and new blindness in adults.1 The cost of direct 11ledical care and lost proCOUNSELING PATIENTS ductivity from diabetes was WIT H estimated to be $20.4 billion in 1987. Care of the patient with diabetes focuses on control of blood glucose levels, which requires appropriate dietalY and lifestyle changes, monitoring blood glucose with the appropriate equipment, and possibly dlUg therapy. 2 Often cOlllplicating this cOlllplex plan of care is the relative lack of access by patients to proper diabetes education. The fragmented system of patient care and patient education that currently exists limits patients' ability to care properly for their disease. Educational requirements must remain individualized and can be provided through a coordinated team effort. Identification of the importance of diabetes education has led to the developlllent of an interdisciplinary organization, the American Association of Diabetes Educators. Pharmacists can playa prilllary role by educating patients with diabetes to become their own day-to-day primary care providers.
DIABETES
Vol. NS31, No. 11 November 1991/813
A "frosting" cataract seen in a young diabetic patient. The white clefts are caused by repeated episodes of hyperglycemia, which traps sorbitol in the lens, eventuaUy making it opaque.
What Is Diabetes? Diabetes is a chronic, long-term disorder of glucose intolerance resulting from loss of insulin production or from inappropriate insulin activity. This glucose intolerance results in changes in the body's energy handling, causing some 11letabolic alterations.
AMERICAN PHARMACY
Diabetes is classified into two types: insulin-dependent diabetes mellitus, or type I; and non-insulin-dependent diabetes mellitus, or type II. Normal fasting glucose levels are between 70 and 120 mgldL; repeated fasting levels above 140 mgldL indicate diabetes. Random glucose determinations of 200 mgldL or higher also indicate diabetes.3 Good contemporary management of diabetes attempts to "normalize" glycemic control, or return blood glucose to a euglycemic range . Ideal control is considered to be the maintenance of levels below 150 mg/ dL; many clinicians consider levels less than 180 mgldL to be acceptable.
mother has diabetes. 2,4,5 Prolonged hyperglycemia also alters the metabolic polyol pathway (Figure 1), stimulating its production of sorbitol. When glucose levels are normal, this pathway is not the major route by which the body's cells handle glucose. When blood sugar is high, however, the routine enzyme systems become saturated, and the myo-inositol pathway is used to reduce glucose to sorbitol. Nerve cells are most affected, because they do not require insulin for glucose absorption. The accumulation of sorbitol in tissue can result in lost functional capacity of the involved tissue, for example, decreased nerve conduction velocity. These effects are seen in diabetic patients whose blood glucose levels are consistently above 150 mgldL. Desired or optimal glucose control is the maintenance of glucose levels at 150 mgldL or lower.
Metabolic Changes
The metabolic changes secondary to diabetes are not limited to the body's handling of glucose. The disease also affects how the body handles fat and protein. The abnormal use of glucose causes prolonged hyperglycemia, which drives other changes in the body's use of energy and results in multiple defects that can affect every organ (see Table 1). A primary effect is an accelerated atherosclerotic process Effects of Hyperglycemia that causes an increased rate in the thickening of the capil• Increased thickening of the capillary basement membrane lary basement membrane, the functional portion of the cap• Glucose metabolized through polyol pathway illary wall. Capillary function thus deteriorates, impairing the • Increased blood viscosity distribution of the blood's nutrients and oxygen and mainte• Decreased red blood cell flexibility nance of proper vascular tone. • Increased fibrinogen levels Hyperglycemia in tum causes glucose to bind to protein in • Altered lipid metabolism, causing increased lipid levels several areas of the body. This process, called glycosylation, • High levels of hemoglobin glycosylation can alter the ability of the protein to function properly. The glycosylated hemoglobin test is used to lTIonitor the relative amount of glucose binding , or relative glycelnic Proposed Mechanisms of Diabetic control. Neur opathy Pathogenesis Hyperglycemia also alters the n1ethod in which lipids HYPERGLYCEMIA are handled. When less glucose enters the body's cells Aldose Reductase for use as energy, the body Microvascular and :::on1pensates with alternative Sorbitol Macrovascular energy use. Stored lipids are Changes Sorbitol Dehydrogenase mobilized , resulting in 1 Neurotrophic increased circulating lipids , Factors 1J Fructose and speeding the atheroscleGlycosylation of rosis process. The ability of Protein Axonal the immune systen1 and ...... . . . . . - - - - - - - Hypoxia • Mv+nOSitOI Atrophy phagocytes to fight infections is also in1paired by hyperNa-K-ATPase glycemia, although the exact Ischemic Nerve lllechanisn1 is unknown. Injury Additionally , the risk of Nerve Conduction Velocity neonatal n10rbidity and mortality is increased when the From Reference 25; used with permission.
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AMERICAN PHARMACY
j
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November 1991/814
Vol. NS31, No. 11
Progression of Complications Diabetes is a heterogeneous condition that produces its effects in many different ways. The association between glucose control and the development of complications is not well understood. It is unclear, for example, why one particular patient develops significant nephrotoxicity, but not other complications of diabetes. The relative risk of complications is affected by the patient's health habits (exercise, diet, etc.), family history (including a history of cardiovascular disease), and other preexisting conditions, such as obesity, high blood pressure, and elevated lipids. The progression of complications in patients with type II diabetes appears to be much more rapid than in those with type I diabetes. The rate is not truly different, however; the insidious nature of the onset of type II diabetes means that complications may occur more quickly after diagnosis, creating the perception of rapid progression. 4 Maintaining glycemic control reduces the risk of complications, but even with good control complications occur. Issues of what is good glycemic control or what are the barometers of good 11lanagement are constantly raised. Assessing the progression of complications is one of the measures of success in the management of diabetic patients. To set better guidelines for this assessment, a multicentered 10-year study, the Diabetes Control and Complications Trial (DCCT) , is underway. The study compares an intensive management program in type I patients with a more traditional regimen. Begun in
1986, the DCCT has enrolled some 1,500 patients from more than 20 U.S. and Canadian care centers. Preliminary results have shown that the tightly managed group does experience hypoglycemic episodes more frequently and th at these episodes are more severe as a result of the tight control. The search for the underlying causes of complications from diabetes will continue.
Major Complications The chronic complications of diabetes can be classified as neurologic or vascular changes. Since these complications are basically alterations in the capabilities of the nerves and the large and small blood vessels, diabetes clearly can alter the function of any organ system of the body.
Neurologic Complications Neurologic changes- neuropathies- are recognized to some degree in approximately 500/0 of patients who have had diabetes for 25 years or more. It is unusual for a patient to have signs of neuropathy within the first five years of onset of diabetes. An exception to this is the patient with type II non-insulin-dependent diabetes whose disease was undiagnosed for several years. Diabetic neuropathies are generally categorized as difTable 2. fuse or focal (Table 2). DifClassification of D iabetic Neuropathies fuse neuropathies include distal symmetrical polyneuType Definition Signs and Symptoms ropathy and autonomic neuDiffuse . ' . ropathies affecting the autonomic nervous system. Distal symmetrica l Affect the nerves of the Burning; sting ing; shooting polyneuropathies lower limbs or stabbing pain ; numbness Focal neuropathies may involve only one or a few A utonomic neuropathies Affect autonomic nerves Cardiovascular Orthostatic hypotension; nerve roots, or they may fixed heart rate; silent involve nerves in a particumyocardial infarctions lar region of the body.6,7 Gastrointestinal Gastroparesis; anorexia; Distal symmetrical polynausea; vom it ing; diarrhea; neuropathies are the most constipation commonly encountered diaGenitourinary Bladder dysfunction; betic neuropathies; 12 0/0 of impotence; retrograde patients develop the condiejaculation tion soon after the onset of Focal diabetes, and nearly 60 0/0 Mononeuropathy Affect single nerve May include tingling, pain, have developed it after 25 burning, and numbness of years. The clinical course of Mononeuropathy Simultaneous disease of several the area affected by the multiplex peripheral nerves polyneuropathies, like that involved nerve of most diabetic n euRadiculopathy Disease of the nerve roots ropathies, generally starts in Plexopathy Disorder of a network or the distal tissue, such as that tangle (plexus) of the feet and toes or fin-
Vol. NS31, No. 11 Novem ber 1991/815
AMERICAN PHARMACY
g rs and hands, with shooting or stabbing pain, tingling, or burning. Commonly, the patient will report more symptoms at night. As nerve damage progresses, neurologic function is re duced to produce almost anesthetic effects (numbness) , and the p atient may not complain of pain. 8 ,9 Table 2 lists the signs and symptoms of common diabetic n uropathies. Note that autonomic neuropathies evoke alterations in many of the activities of the body that are normally regulated by the autonomic nervous system. The precise mechanism for the neuropathies has not been fully defined, but several contributing factors have been identified.5,8,lO The myo-inositol system seems to be important in initiating a neuropathic reaction. Although insulin is required for most cells to absorb glucose, it is not required for glucose absorption by nerve cells. Figure 1 illustrates the myo-inositol pathway and other possible explanations for n europathy. As protein i glycosylated, the protein is less able to function opti-
mally for the intended purpose, and nerve conduction velocity is slowed. A decreased nerve function, perhaps caused by the nervous system's regulation of nutrition and maintenance of tissue-neurotrophic factors--has also been noted. Treatment of neuropathies is largely aimed at relief of symptoms and is dictated by the type of neuropathy experienced. The cornerstone of therapy for all neuropathies, however, is the tight management of d iabetes for good glycemic control in an effort to reduce or slow the incidence of n eu ropathy. Medications that have been tested for diabetic neuropathies include tricyclic antidepressants, phenothiazines, ph enytoin , carbamazep ine, nonsteroidal antiinflammatory agents, and capsaicin. Of these, none appears to be a superior therapeutic agent for a given neuropathy; individual p atients benefit from different agents. The antidepressants are usually the first agents used. 9,lO One category of agents now being investigated for neu-
Developing a Diabetes Center Deciding whether to establish a diabetes care center in your phannacy requires assessment of your commitment and knowledge, as well as of the need for a center. An in1pOltant consideration in developing a diabetes center is just how Inuch involvement you personally want to have. The fu ll implementation of a counseling program will require the cooperation and training of other members of your staff as well. First, assess your interest and Inotivation. A commitment to developing a diabetes care center requires support. Requiren1ents will include the developlnent of a n1ethod to stay up to date with current and new trends in diabetes care, assessment of your ability to counsel patients with diabetes, and a concern for each of the patients you will ncounter in your practice . Questions that you need to answer include: • How n1uch do you currently know about the clinical management of diabetes? • How much effolt will be required to become highly knowledgeable about the clinical aspects of diabetes? • How much do you know about the currently available products used for diabetes care? • Do you know the benefits and the limitations of the diabetes products you currently stock? • What members of your staff Inust becon1e knowledgeable about diabetes care and products? The answers to these questions and other considerations, such as the local demographics of patients with diabetes, will largely determine your decision to begin developing a program. If the answer is yes, you may want to consider working with two organizations-the American Diabetes Association and the American Association of Diabetes Educators. Their professional education is aimed at supporting and fostering optimal education and care of diabetic patients. Once you have decided to establish a center, the first step is to decide what products you will add for the center. Are there particular products that you or other care providers in your network prefer? What companies provide quality
AMERICAN PHARMACY
Phannacist R Keith CampbeU counsels younger patients about diabetes.
patient information with their products? The diabetes products you provide should be grouped together on at least four 4-foot shelves placed close to the prescription area for easy access. Highlight this area with signs and information about the products. Crucial to the success of a diabetes care center is development of a separate area for individual patient counseling. This area is used for patient teaching, equipment demonstration, and any "how to's" that arise. As your program gets underway, make sure other health care providers with whom you interact know of the program. Be sure to advertise not only your equipment, but your other valuable product-your knowledge and counseling expertise.
November 1991/816
Vol. NS31, No. 11
ro pathies is the aldose reductase inhibitors-tolrestat, sorbinil, statil, and alrestatin. By altering the function of the myo-inositol pathway, these agents slow the forn1ation of sorbitol in the cell. Clinical results are mixed, however, and side effects, especially hypersensitivity, can be significant. Autonomic neuropathies can affect areas throughout the autonolnic nervous system. Gastroparesis and diabetic diarrhea are two exan1ples of these effects within the gastrointestinal tract. Metoclopran1ide is often used for gastroparesis changes. Autonomic neuropathies can also alter cardiovascular function and bladder control and can induce impotence. Therapy for autonomic neuropathies includes treating the syn1ptoms or signs of the neuropathy, such as treating diabetic diarrhea with a bulk-forming laxative. Impotence may also be caused by medication; a review of the patient's profile may help identify an agent that can induce impotence. 9
Table 3.
Clinical Course of Diabetic Nephropathy Phase
Characteristics
Preclinical
Duration-5 to 8 years Renal Hypertrophy Hype rfi Itrati 0 n Glomerular filtration rate-normal or high Blood pressure- normal Urinary albumin excret ion- normal
Incipient
Duration-5 to 10 years Microalbuminuria (40- 400 mg/24 h) Blood pressure- may be elevated Probably reversibl e
Vascular Complications
Cl in ical
Duration-8 to 17 yea rs Proteinuria (album in >500 mg/24 h)
Diabetic Retinopathy
Diabetic retinopathy is the most comn10n complication of diabetes. Approxin1ately 700,000 people have proliferative diabetic retinopathy, and its incidence increases with the patient's age and the duration of disease. Over a lifetin1e, 70% of people with type I diabetes will develop proliferative diabetic retinopathy. \Vide-angle glaucoma is also 1.4 titnes n10re con1n10n in patients with diabetes. Retinopathy is divided broadly into two categories: background, or nonproliferative; and proliferative. 11 ,12 Nonproliferative disease results froln years of vascular insult caused by hyperglycen1ia-related damage to the capillary basement n1elnbrane. Proliferative retinopathy apparently involves a lTIOre intensive, pronounced reaction secondary to angiogenic factors not yet isolated. These factors apparently induce profound changes that in turn induce the proliferative changes. The pathogenesis appears to be a con1bination of hypoxia and the overproduction of sorbitol by the myo-inositol pathway, but also involves a microvascular effect resulting from diabetes-induced changes in the integrity of blood viscosity and of sn1all blood vessels. Retinal laser surgery may be needed to correct the retinopathy but should be considered only if long-term attempts to control glucose levels have failed. Maintaining norn1al blood pressure lessens the effect of changes in the sn1all blood vessels. The risk of retinopathy and other vascular complications is significantly reduced when blood pressure and blood glucose are controlled.13 ,14 Annual eye examinations for all diabetes patients are required. Recently, a steering committee of the National Eye Institute and the National Eye Health Education Program has
Vol. NS31, No. 11 Novembe r 1991/817
Glomerular fi ltration rate declin es 7-30 mUmin/yr Hypertension Progression to end -stage renal disease
been developing an educational progran1 to in1prove patient eye care. Once it is available, phannacists will have the opportunity to becon1e n10re involved in educating patients about their eye care needs. Nephropathy
The kidneys are affected by changes in the vascular systen1 induced by many diseases, including diabetes. Diabe tic nephropathy can lead to end-stage renal disease (Table 3), the incidence of which approaches 40% in persons who have had type I diabetes for 20 years. Diabetic patients should therefore be closely monitored for signs of this complication. The use of n1edications that alter renal function or decrease renal blood flow should be avoided or lin1ited. All patients should be encouraged to continue good glycelnic control and to check regularly with their physician for urine testing. Therapy includes lin1iting protein intake to curtail its effects on renal perfusion and vasodilation, one cause of glon1erular damage and proteinuria. 15 ,16 As with other con1plications of diabetes, the myo-inositol pathway n1ay play a role in the development of diabetic nephropathy. The aldose reductase inhibitors under investigation may therefore be beneficial in controlling this complication. Evidence that angiotensin-converting enzyn1e (ACE) inhibitors lower intraglomerular capillalY pressure to possibly slow kidney tissue damage has
AMERICAN PHARMACY
spark d their use in the early stages of diabetic nephropathy, although long-tenn benefit has not been demonstrated . Other Vascular Complications
The incidence of hypertension in patients w ith diabetes is twice as frequent as that in the general population. When an antihypertensive agent is needed, selecting one that positively affects the renal systen1 , does not adversely alter glycemic control, and positively affects serum lipids can be difficult. Table 4 sun1marizes son1e of the actions of various antihypertensive agents and a therapy plan .17-20 Poorly controlled diabetes can affect the peripheral vascular system. Resultant alteratio ns in the blood's viscosity and elythrocyte function predisposes the patient to claudication, Raynaud's phenomenon, and other exacerbations of poor blood flow or function, as well as mobilized lipids.21 ,22 Several centers advocate testing for and identification of peripheral vascular disease and treatn1ent with a hen10rrheologic agent such as pentoxifylline.23 This agent, given at 400 mg, three times daily, enhances peripheral blood flow . The principles of management of peripheral vascular dis-
ease are regular diet and exercise and cessation of sn10king. Cardiovascular disease is the leading cause of morbidity and mortality in patie nts with diabetes. The risk of death from cardiovascu lar disease is two to three tin1es greater in patients with diabetes, n1agnifying the need for good hypertension and lipid control and elin1ination of sn10king.
Diabetic Foot Disease Diabetic foot disease is a co n1plication of di a betes induced by changes in both neurologic and vascular systen1S. COlnn10n signs of progressive foot disease include: • Loss of protective sensation • Autonon1ic neuropathy • Previous ulcer or alnputation • Foot deforn1ity • Neuropathic fractures • High p lantar fissures • Vascular disease • Inadequate foot wear Table 4.
Diabetes and Hypertension Therapy Considerations Step One Start with a small dose of: • Thiazide diuretic, OR • Beta blocker, OR • ACE inhibitor, alpha, receptor antagonist, calcium blocker
Step Two If blood pressure is not controlled to the desired level, then increase dose OR add: • ACE inhibitor, calcium channel blocker, adrenergic inhibitor, OR • Thiazide diuretic if not the step-one agent Now the patient would be taking a thiazide diuretic and one other agent for hypertension.
Step Three If blood pressure control is still not achieved, then increase the doses or add:
Thiazide diuretics have traditionally been considered the agents of first choice for hypertension, but some exceptions exist. With diabetes, glycemic control can be worsened, with hypokalemia and magnesemia also produced. If the patient requires diuresis, adjustment of the glycemic agent may be necessary and potassium and magnesium supplementation required. Preferred agents in this step if initial diuresis is not needed are the ACE inhibitors and calcium channel blockers that have no direct glycemic effect (note that the beta blockers do affect blood glucose) and have neutral to positive lipid effects. The step-two agent choices would be to add a diuretic if a nondiuretic was the step-one choice. Each of the nondiuretic agents work better when combined with a diuretic, since they all can cause fluid retention. Other choices are based on the patient's other preexisting conditions. Any of the alpha-adrenergic blocking agents can induce autonomic side effects, including orthostasis and impotence, and should be used only if necessary in the diabetes population with preexisting autonomic neuropathy.
Step three is reserved for the addition of a vasodilator in most cases-either hydralazine or minoxidil. The potential for producing tachycardia from these drugs must be monitored.
• Vasodilator or a beta blocker
Step Four Following these steps, referral to a vascular specialist for the refractory hypertension case is recommended.
Adapted from Reference 15.
AMERICAN PHARMACY
No vember 1991/ 8 18
Vol. NS31, No. 11
• Vision loss • Inadequate glyceluic control • Altered foot function. Of 100,000 nontraumatic an1putations perfonued in the United States each year, 50% are fron1 complications of diabetes, and half of those are preventable. A priluary concern is lack of instruction of patients with diabetes. 24 This often results fron1 health care providers' ass un1ption that patients know luore about their disease than they actually do. Ask your patients to inspect their feet daily for any noticeable changes. Recon1mend lotions that keep the feet hydrated but don't irritate the skin. Discuss with patients how they should trin1 their toenails . Recommend that they remove their shoes and socks on every visit to a physician so their feet will be examined.
Diabetes Care and Complications Checklist Questions to ask your patients with diabetes, on either the first visit or return visits, and include in their profile to routinely update and remind them of health tips: -How long have you had diabetes? (new patient) -Tell me how you care for your diabetes. -How do you feel about caring for your diabetes? -How does your family feel about your diabetes? -Do you have any signs or symptoms of diabetes or any involvement with the organ systems? (Give examples.) -When was your last examination by an ophth'a lmologist? Do you have an eye examination scheduled, and do you understand why it is important to you? (Review the patient's medication profile for any drug that can induce changes in vision or exacerbate ophthalmic problems.) -Do you smoke? Here are some considerations for limiting or stopping your smoking to better care for your diabetes. -Do you take other medications? (Check to see if any of the other medica tions could be for a neuropathy. If so, find out how the patient is responding to therapy.) -Do you have high blood pressure? If so, what are your Jlmagic numbers"? (Make sure the patient understands the vital need for keeping both blood pressure and glucose levels well controlled. -What medications are you using for controlling your blood pressure? How well are these medications working for you?
Conclusions The chronic complications of diabetes can significantly affect a patient's lifestyle . These problelus must be aggressively prevented through tight glycemic control and education and treated when they do occur. Information should be included in profiles of diabetic patients to determine education and therapy needs. Basic questions to ask to gather this information are listed in Table 5. Counseling must include in1proving a patient's understanding of the complications of diabetes and those factors contributing to their developD1ent. If a patient discusses
VoL NS31, No. 11 Novem ber 1991/819
-When was the last time you checked your feet? How often do you examine your feet? (Make sure to review the following with the patient: - The correct way to trim/clip their toenails - The need for daily foot examination - Proper hydration/lotion to their feet - How to test water temperature - The need to avoid walking barefooted - The need to avoidance of chemical wart removers - How to break in new shoes - The need for the patient's feet to be checked by the physician at each visit.) -Do you test your urine for protein? Have you been told to test for this problem? If so, what do you include in your diet plan? -What blood glucose testing system method do you use? Any?
AMERICAN PHARMA
one of the health care changes that have occurred in recent years has been more dramatic than the recognition that chronic disorders have beCOllle a n1ajor concern and that education is the key to dealing with them. The third leading cause of death due to disease in America is the chronic disorder diabetes mellitus and its complications. All of the n1ajor organ systems in the body can be dan1aged by diabetes. Diabetes is the single n10st comn1on cause of renal failure in the United States and is the leading cause of nontraun1atic amputations and new blindness in adults.1 The cost of direct 11ledical care and lost proCOUNSELING PATIENTS ductivity from diabetes was WIT H estimated to be $20.4 billion in 1987. Care of the patient with diabetes focuses on control of blood glucose levels, which requires appropriate dietalY and lifestyle changes, monitoring blood glucose with the appropriate equipment, and possibly dlUg therapy. 2 Often cOlllplicating this cOlllplex plan of care is the relative lack of access by patients to proper diabetes education. The fragmented system of patient care and patient education that currently exists limits patients' ability to care properly for their disease. Educational requirements must remain individualized and can be provided through a coordinated team effort. Identification of the importance of diabetes education has led to the developlllent of an interdisciplinary organization, the American Association of Diabetes Educators. Pharmacists can playa prilllary role by educating patients with diabetes to become their own day-to-day primary care providers.
DIABETES
Vol. NS31, No. 11 November 1991/813
A "frosting" cataract seen in a young diabetic patient. The white clefts are caused by repeated episodes of hyperglycemia, which traps sorbitol in the lens, eventuaUy making it opaque.
What Is Diabetes? Diabetes is a chronic, long-term disorder of glucose intolerance resulting from loss of insulin production or from inappropriate insulin activity. This glucose intolerance results in changes in the body's energy handling, causing some 11letabolic alterations.
AMERICAN PHARMACY
Diabetes is classified into two types: insulin-dependent diabetes mellitus, or type I; and non-insulin-dependent diabetes mellitus, or type II. Normal fasting glucose levels are between 70 and 120 mgldL; repeated fasting levels above 140 mgldL indicate diabetes. Random glucose determinations of 200 mgldL or higher also indicate diabetes.3 Good contemporary management of diabetes attempts to "normalize" glycemic control, or return blood glucose to a euglycemic range . Ideal control is considered to be the maintenance of levels below 150 mg/ dL; many clinicians consider levels less than 180 mgldL to be acceptable.
mother has diabetes. 2,4,5 Prolonged hyperglycemia also alters the metabolic polyol pathway (Figure 1), stimulating its production of sorbitol. When glucose levels are normal, this pathway is not the major route by which the body's cells handle glucose. When blood sugar is high, however, the routine enzyme systems become saturated, and the myo-inositol pathway is used to reduce glucose to sorbitol. Nerve cells are most affected, because they do not require insulin for glucose absorption. The accumulation of sorbitol in tissue can result in lost functional capacity of the involved tissue, for example, decreased nerve conduction velocity. These effects are seen in diabetic patients whose blood glucose levels are consistently above 150 mgldL. Desired or optimal glucose control is the maintenance of glucose levels at 150 mgldL or lower.
Metabolic Changes
The metabolic changes secondary to diabetes are not limited to the body's handling of glucose. The disease also affects how the body handles fat and protein. The abnormal use of glucose causes prolonged hyperglycemia, which drives other changes in the body's use of energy and results in multiple defects that can affect every organ (see Table 1). A primary effect is an accelerated atherosclerotic process Effects of Hyperglycemia that causes an increased rate in the thickening of the capil• Increased thickening of the capillary basement membrane lary basement membrane, the functional portion of the cap• Glucose metabolized through polyol pathway illary wall. Capillary function thus deteriorates, impairing the • Increased blood viscosity distribution of the blood's nutrients and oxygen and mainte• Decreased red blood cell flexibility nance of proper vascular tone. • Increased fibrinogen levels Hyperglycemia in tum causes glucose to bind to protein in • Altered lipid metabolism, causing increased lipid levels several areas of the body. This process, called glycosylation, • High levels of hemoglobin glycosylation can alter the ability of the protein to function properly. The glycosylated hemoglobin test is used to lTIonitor the relative amount of glucose binding , or relative glycelnic Proposed Mechanisms of Diabetic control. Neur opathy Pathogenesis Hyperglycemia also alters the n1ethod in which lipids HYPERGLYCEMIA are handled. When less glucose enters the body's cells Aldose Reductase for use as energy, the body Microvascular and :::on1pensates with alternative Sorbitol Macrovascular energy use. Stored lipids are Changes Sorbitol Dehydrogenase mobilized , resulting in 1 Neurotrophic increased circulating lipids , Factors 1J Fructose and speeding the atheroscleGlycosylation of rosis process. The ability of Protein Axonal the immune systen1 and ...... . . . . . - - - - - - - Hypoxia • Mv+nOSitOI Atrophy phagocytes to fight infections is also in1paired by hyperNa-K-ATPase glycemia, although the exact Ischemic Nerve lllechanisn1 is unknown. Injury Additionally , the risk of Nerve Conduction Velocity neonatal n10rbidity and mortality is increased when the From Reference 25; used with permission.
l
t
l
t
t
+
--
AMERICAN PHARMACY
j
~
j
November 1991/814
Vol. NS31, No. 11
Progression of Complications Diabetes is a heterogeneous condition that produces its effects in many different ways. The association between glucose control and the development of complications is not well understood. It is unclear, for example, why one particular patient develops significant nephrotoxicity, but not other complications of diabetes. The relative risk of complications is affected by the patient's health habits (exercise, diet, etc.), family history (including a history of cardiovascular disease), and other preexisting conditions, such as obesity, high blood pressure, and elevated lipids. The progression of complications in patients with type II diabetes appears to be much more rapid than in those with type I diabetes. The rate is not truly different, however; the insidious nature of the onset of type II diabetes means that complications may occur more quickly after diagnosis, creating the perception of rapid progression. 4 Maintaining glycemic control reduces the risk of complications, but even with good control complications occur. Issues of what is good glycemic control or what are the barometers of good 11lanagement are constantly raised. Assessing the progression of complications is one of the measures of success in the management of diabetic patients. To set better guidelines for this assessment, a multicentered 10-year study, the Diabetes Control and Complications Trial (DCCT) , is underway. The study compares an intensive management program in type I patients with a more traditional regimen. Begun in
1986, the DCCT has enrolled some 1,500 patients from more than 20 U.S. and Canadian care centers. Preliminary results have shown that the tightly managed group does experience hypoglycemic episodes more frequently and th at these episodes are more severe as a result of the tight control. The search for the underlying causes of complications from diabetes will continue.
Major Complications The chronic complications of diabetes can be classified as neurologic or vascular changes. Since these complications are basically alterations in the capabilities of the nerves and the large and small blood vessels, diabetes clearly can alter the function of any organ system of the body.
Neurologic Complications Neurologic changes- neuropathies- are recognized to some degree in approximately 500/0 of patients who have had diabetes for 25 years or more. It is unusual for a patient to have signs of neuropathy within the first five years of onset of diabetes. An exception to this is the patient with type II non-insulin-dependent diabetes whose disease was undiagnosed for several years. Diabetic neuropathies are generally categorized as difTable 2. fuse or focal (Table 2). DifClassification of D iabetic Neuropathies fuse neuropathies include distal symmetrical polyneuType Definition Signs and Symptoms ropathy and autonomic neuDiffuse . ' . ropathies affecting the autonomic nervous system. Distal symmetrica l Affect the nerves of the Burning; sting ing; shooting polyneuropathies lower limbs or stabbing pain ; numbness Focal neuropathies may involve only one or a few A utonomic neuropathies Affect autonomic nerves Cardiovascular Orthostatic hypotension; nerve roots, or they may fixed heart rate; silent involve nerves in a particumyocardial infarctions lar region of the body.6,7 Gastrointestinal Gastroparesis; anorexia; Distal symmetrical polynausea; vom it ing; diarrhea; neuropathies are the most constipation commonly encountered diaGenitourinary Bladder dysfunction; betic neuropathies; 12 0/0 of impotence; retrograde patients develop the condiejaculation tion soon after the onset of Focal diabetes, and nearly 60 0/0 Mononeuropathy Affect single nerve May include tingling, pain, have developed it after 25 burning, and numbness of years. The clinical course of Mononeuropathy Simultaneous disease of several the area affected by the multiplex peripheral nerves polyneuropathies, like that involved nerve of most diabetic n euRadiculopathy Disease of the nerve roots ropathies, generally starts in Plexopathy Disorder of a network or the distal tissue, such as that tangle (plexus) of the feet and toes or fin-
Vol. NS31, No. 11 Novem ber 1991/815
AMERICAN PHARMACY
g rs and hands, with shooting or stabbing pain, tingling, or burning. Commonly, the patient will report more symptoms at night. As nerve damage progresses, neurologic function is re duced to produce almost anesthetic effects (numbness) , and the p atient may not complain of pain. 8 ,9 Table 2 lists the signs and symptoms of common diabetic n uropathies. Note that autonomic neuropathies evoke alterations in many of the activities of the body that are normally regulated by the autonomic nervous system. The precise mechanism for the neuropathies has not been fully defined, but several contributing factors have been identified.5,8,lO The myo-inositol system seems to be important in initiating a neuropathic reaction. Although insulin is required for most cells to absorb glucose, it is not required for glucose absorption by nerve cells. Figure 1 illustrates the myo-inositol pathway and other possible explanations for n europathy. As protein i glycosylated, the protein is less able to function opti-
mally for the intended purpose, and nerve conduction velocity is slowed. A decreased nerve function, perhaps caused by the nervous system's regulation of nutrition and maintenance of tissue-neurotrophic factors--has also been noted. Treatment of neuropathies is largely aimed at relief of symptoms and is dictated by the type of neuropathy experienced. The cornerstone of therapy for all neuropathies, however, is the tight management of d iabetes for good glycemic control in an effort to reduce or slow the incidence of n eu ropathy. Medications that have been tested for diabetic neuropathies include tricyclic antidepressants, phenothiazines, ph enytoin , carbamazep ine, nonsteroidal antiinflammatory agents, and capsaicin. Of these, none appears to be a superior therapeutic agent for a given neuropathy; individual p atients benefit from different agents. The antidepressants are usually the first agents used. 9,lO One category of agents now being investigated for neu-
Developing a Diabetes Center Deciding whether to establish a diabetes care center in your phannacy requires assessment of your commitment and knowledge, as well as of the need for a center. An in1pOltant consideration in developing a diabetes center is just how Inuch involvement you personally want to have. The fu ll implementation of a counseling program will require the cooperation and training of other members of your staff as well. First, assess your interest and Inotivation. A commitment to developing a diabetes care center requires support. Requiren1ents will include the developlnent of a n1ethod to stay up to date with current and new trends in diabetes care, assessment of your ability to counsel patients with diabetes, and a concern for each of the patients you will ncounter in your practice . Questions that you need to answer include: • How n1uch do you currently know about the clinical management of diabetes? • How much effolt will be required to become highly knowledgeable about the clinical aspects of diabetes? • How much do you know about the currently available products used for diabetes care? • Do you know the benefits and the limitations of the diabetes products you currently stock? • What members of your staff Inust becon1e knowledgeable about diabetes care and products? The answers to these questions and other considerations, such as the local demographics of patients with diabetes, will largely determine your decision to begin developing a program. If the answer is yes, you may want to consider working with two organizations-the American Diabetes Association and the American Association of Diabetes Educators. Their professional education is aimed at supporting and fostering optimal education and care of diabetic patients. Once you have decided to establish a center, the first step is to decide what products you will add for the center. Are there particular products that you or other care providers in your network prefer? What companies provide quality
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Phannacist R Keith CampbeU counsels younger patients about diabetes.
patient information with their products? The diabetes products you provide should be grouped together on at least four 4-foot shelves placed close to the prescription area for easy access. Highlight this area with signs and information about the products. Crucial to the success of a diabetes care center is development of a separate area for individual patient counseling. This area is used for patient teaching, equipment demonstration, and any "how to's" that arise. As your program gets underway, make sure other health care providers with whom you interact know of the program. Be sure to advertise not only your equipment, but your other valuable product-your knowledge and counseling expertise.
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ro pathies is the aldose reductase inhibitors-tolrestat, sorbinil, statil, and alrestatin. By altering the function of the myo-inositol pathway, these agents slow the forn1ation of sorbitol in the cell. Clinical results are mixed, however, and side effects, especially hypersensitivity, can be significant. Autonomic neuropathies can affect areas throughout the autonolnic nervous system. Gastroparesis and diabetic diarrhea are two exan1ples of these effects within the gastrointestinal tract. Metoclopran1ide is often used for gastroparesis changes. Autonomic neuropathies can also alter cardiovascular function and bladder control and can induce impotence. Therapy for autonomic neuropathies includes treating the syn1ptoms or signs of the neuropathy, such as treating diabetic diarrhea with a bulk-forming laxative. Impotence may also be caused by medication; a review of the patient's profile may help identify an agent that can induce impotence. 9
Table 3.
Clinical Course of Diabetic Nephropathy Phase
Characteristics
Preclinical
Duration-5 to 8 years Renal Hypertrophy Hype rfi Itrati 0 n Glomerular filtration rate-normal or high Blood pressure- normal Urinary albumin excret ion- normal
Incipient
Duration-5 to 10 years Microalbuminuria (40- 400 mg/24 h) Blood pressure- may be elevated Probably reversibl e
Vascular Complications
Cl in ical
Duration-8 to 17 yea rs Proteinuria (album in >500 mg/24 h)
Diabetic Retinopathy
Diabetic retinopathy is the most comn10n complication of diabetes. Approxin1ately 700,000 people have proliferative diabetic retinopathy, and its incidence increases with the patient's age and the duration of disease. Over a lifetin1e, 70% of people with type I diabetes will develop proliferative diabetic retinopathy. \Vide-angle glaucoma is also 1.4 titnes n10re con1n10n in patients with diabetes. Retinopathy is divided broadly into two categories: background, or nonproliferative; and proliferative. 11 ,12 Nonproliferative disease results froln years of vascular insult caused by hyperglycen1ia-related damage to the capillary basement n1elnbrane. Proliferative retinopathy apparently involves a lTIOre intensive, pronounced reaction secondary to angiogenic factors not yet isolated. These factors apparently induce profound changes that in turn induce the proliferative changes. The pathogenesis appears to be a con1bination of hypoxia and the overproduction of sorbitol by the myo-inositol pathway, but also involves a microvascular effect resulting from diabetes-induced changes in the integrity of blood viscosity and of sn1all blood vessels. Retinal laser surgery may be needed to correct the retinopathy but should be considered only if long-term attempts to control glucose levels have failed. Maintaining norn1al blood pressure lessens the effect of changes in the sn1all blood vessels. The risk of retinopathy and other vascular complications is significantly reduced when blood pressure and blood glucose are controlled.13 ,14 Annual eye examinations for all diabetes patients are required. Recently, a steering committee of the National Eye Institute and the National Eye Health Education Program has
Vol. NS31, No. 11 Novembe r 1991/817
Glomerular fi ltration rate declin es 7-30 mUmin/yr Hypertension Progression to end -stage renal disease
been developing an educational progran1 to in1prove patient eye care. Once it is available, phannacists will have the opportunity to becon1e n10re involved in educating patients about their eye care needs. Nephropathy
The kidneys are affected by changes in the vascular systen1 induced by many diseases, including diabetes. Diabe tic nephropathy can lead to end-stage renal disease (Table 3), the incidence of which approaches 40% in persons who have had type I diabetes for 20 years. Diabetic patients should therefore be closely monitored for signs of this complication. The use of n1edications that alter renal function or decrease renal blood flow should be avoided or lin1ited. All patients should be encouraged to continue good glycelnic control and to check regularly with their physician for urine testing. Therapy includes lin1iting protein intake to curtail its effects on renal perfusion and vasodilation, one cause of glon1erular damage and proteinuria. 15 ,16 As with other con1plications of diabetes, the myo-inositol pathway n1ay play a role in the development of diabetic nephropathy. The aldose reductase inhibitors under investigation may therefore be beneficial in controlling this complication. Evidence that angiotensin-converting enzyn1e (ACE) inhibitors lower intraglomerular capillalY pressure to possibly slow kidney tissue damage has
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spark d their use in the early stages of diabetic nephropathy, although long-tenn benefit has not been demonstrated . Other Vascular Complications
The incidence of hypertension in patients w ith diabetes is twice as frequent as that in the general population. When an antihypertensive agent is needed, selecting one that positively affects the renal systen1 , does not adversely alter glycemic control, and positively affects serum lipids can be difficult. Table 4 sun1marizes son1e of the actions of various antihypertensive agents and a therapy plan .17-20 Poorly controlled diabetes can affect the peripheral vascular system. Resultant alteratio ns in the blood's viscosity and elythrocyte function predisposes the patient to claudication, Raynaud's phenomenon, and other exacerbations of poor blood flow or function, as well as mobilized lipids.21 ,22 Several centers advocate testing for and identification of peripheral vascular disease and treatn1ent with a hen10rrheologic agent such as pentoxifylline.23 This agent, given at 400 mg, three times daily, enhances peripheral blood flow . The principles of management of peripheral vascular dis-
ease are regular diet and exercise and cessation of sn10king. Cardiovascular disease is the leading cause of morbidity and mortality in patie nts with diabetes. The risk of death from cardiovascu lar disease is two to three tin1es greater in patients with diabetes, n1agnifying the need for good hypertension and lipid control and elin1ination of sn10king.
Diabetic Foot Disease Diabetic foot disease is a co n1plication of di a betes induced by changes in both neurologic and vascular systen1S. COlnn10n signs of progressive foot disease include: • Loss of protective sensation • Autonon1ic neuropathy • Previous ulcer or alnputation • Foot deforn1ity • Neuropathic fractures • High p lantar fissures • Vascular disease • Inadequate foot wear Table 4.
Diabetes and Hypertension Therapy Considerations Step One Start with a small dose of: • Thiazide diuretic, OR • Beta blocker, OR • ACE inhibitor, alpha, receptor antagonist, calcium blocker
Step Two If blood pressure is not controlled to the desired level, then increase dose OR add: • ACE inhibitor, calcium channel blocker, adrenergic inhibitor, OR • Thiazide diuretic if not the step-one agent Now the patient would be taking a thiazide diuretic and one other agent for hypertension.
Step Three If blood pressure control is still not achieved, then increase the doses or add:
Thiazide diuretics have traditionally been considered the agents of first choice for hypertension, but some exceptions exist. With diabetes, glycemic control can be worsened, with hypokalemia and magnesemia also produced. If the patient requires diuresis, adjustment of the glycemic agent may be necessary and potassium and magnesium supplementation required. Preferred agents in this step if initial diuresis is not needed are the ACE inhibitors and calcium channel blockers that have no direct glycemic effect (note that the beta blockers do affect blood glucose) and have neutral to positive lipid effects. The step-two agent choices would be to add a diuretic if a nondiuretic was the step-one choice. Each of the nondiuretic agents work better when combined with a diuretic, since they all can cause fluid retention. Other choices are based on the patient's other preexisting conditions. Any of the alpha-adrenergic blocking agents can induce autonomic side effects, including orthostasis and impotence, and should be used only if necessary in the diabetes population with preexisting autonomic neuropathy.
Step three is reserved for the addition of a vasodilator in most cases-either hydralazine or minoxidil. The potential for producing tachycardia from these drugs must be monitored.
• Vasodilator or a beta blocker
Step Four Following these steps, referral to a vascular specialist for the refractory hypertension case is recommended.
Adapted from Reference 15.
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• Vision loss • Inadequate glyceluic control • Altered foot function. Of 100,000 nontraumatic an1putations perfonued in the United States each year, 50% are fron1 complications of diabetes, and half of those are preventable. A priluary concern is lack of instruction of patients with diabetes. 24 This often results fron1 health care providers' ass un1ption that patients know luore about their disease than they actually do. Ask your patients to inspect their feet daily for any noticeable changes. Recon1mend lotions that keep the feet hydrated but don't irritate the skin. Discuss with patients how they should trin1 their toenails . Recommend that they remove their shoes and socks on every visit to a physician so their feet will be examined.
Diabetes Care and Complications Checklist Questions to ask your patients with diabetes, on either the first visit or return visits, and include in their profile to routinely update and remind them of health tips: -How long have you had diabetes? (new patient) -Tell me how you care for your diabetes. -How do you feel about caring for your diabetes? -How does your family feel about your diabetes? -Do you have any signs or symptoms of diabetes or any involvement with the organ systems? (Give examples.) -When was your last examination by an ophth'a lmologist? Do you have an eye examination scheduled, and do you understand why it is important to you? (Review the patient's medication profile for any drug that can induce changes in vision or exacerbate ophthalmic problems.) -Do you smoke? Here are some considerations for limiting or stopping your smoking to better care for your diabetes. -Do you take other medications? (Check to see if any of the other medica tions could be for a neuropathy. If so, find out how the patient is responding to therapy.) -Do you have high blood pressure? If so, what are your Jlmagic numbers"? (Make sure the patient understands the vital need for keeping both blood pressure and glucose levels well controlled. -What medications are you using for controlling your blood pressure? How well are these medications working for you?
Conclusions The chronic complications of diabetes can significantly affect a patient's lifestyle . These problelus must be aggressively prevented through tight glycemic control and education and treated when they do occur. Information should be included in profiles of diabetic patients to determine education and therapy needs. Basic questions to ask to gather this information are listed in Table 5. Counseling must include in1proving a patient's understanding of the complications of diabetes and those factors contributing to their developD1ent. If a patient discusses
VoL NS31, No. 11 Novem ber 1991/819
-When was the last time you checked your feet? How often do you examine your feet? (Make sure to review the following with the patient: - The correct way to trim/clip their toenails - The need for daily foot examination - Proper hydration/lotion to their feet - How to test water temperature - The need to avoid walking barefooted - The need to avoidance of chemical wart removers - How to break in new shoes - The need for the patient's feet to be checked by the physician at each visit.) -Do you test your urine for protein? Have you been told to test for this problem? If so, what do you include in your diet plan? -What blood glucose testing system method do you use? Any?
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